Project Summary Research: Stress hyperglycemia is common in the perioperative period and is associated with increased risk of postoperative mortality. Counterregulatory hormones and inflammatory mediators appear to modulate the acute biological response to stress; however, the pathophysiological pathways that result in stress hyperglycemia and its link to poor clinical outcomes are not well understood. Comprehensive metabolic profiling (metabolomics) represents a novel tool to examine metabolic changes during stress conditions. The current approach to treat hyperglycemia with insulin has major limitations including high resource utilization and high risk of hypoglycemia. The overarching hypotheses of this research proposal are that: 1) Stress-hyperglycemia is associated with changes in unknown and known metabolites (i.e. branched-chain amino acids, acylcarnitines, ceramides) and path-specific biomarkers (representing inflammation,!coagulation, cell stress, and immune modulation) in the perioperative period in cardiac surgery patients, and 2) with a low risk of iatrogenic hypoglycemia, exposure to a long acting glucagon like peptide-1 receptor agonist (GLP-1 RA) will ameliorate the hyperglycemic and inflammatory response to surgical stress. Using comprehensive metabolic profiling methods, this study will provide new insights into the mechanisms underlying the metabolic and inflammatory responses to surgical stress (Aim 1). This study will also examine whether exposure to a long acting GLP-1 RA can improve glycemic control and ameliorate the inflammatory response to acute surgical stress (Aim 2). These findings will provide proof-of principle to support the use of novel therapies to prevent and manage stress hyperglycemia in the inpatient setting. Candidate and Environment: The candidate for this K23 award is Francisco J Pasquel, MD, MPH, a highly qualified endocrinologist at Emory University committed to developing a career as an independently funded translational researcher. The goal of this proposal is to provide the candidate with additional advanced mentored training to develop expertise in mechanistic aspects of the metabolic response to stress and the design and execution of complex clinical studies. Key components of the training plan include: 1) mentorship from investigators with expertise in metabolomics, biomarkers, and clinical trials; 2) learning skills in bioinformatics, metabolomics!and network analysis, and grant writing through advanced coursework; 3) hands-on experience metabolomics research, and design/execution of a nested case-control study and a clinical trial; and 4) participation in scholarly activities to develop independent research projects, and formulate NIH applications. To successfully achieve his goals, the candidate has assembled a multidisciplinary and committed group of Mentors, all of whom have successfully mentored junior investigators, have a strong track record of independent funding, and are internationally recognized experts in all areas of research related to this project. The project will take place at Emory University, a highly collaborative academic environment that provides an ideal setting to support Dr. Pasquel's training and research needs.